Influenza viruses (“flu” for short) are one of the most threatening viruses against humans life. Four influenza pandemics occurred since the 20th century, respectively in 1918˜1919 (Spanish flu, H1N1), 1957 (Asian flu, H2N2), 1968 (Hong Kong flu, H3N2) and 1977 (Russian flu, H1N1), of which the 1918 Spanish flu was the most serious pandemic, wherein its H1N1 viral strain was mutated from avian influenza and human influenza virus, and the influenza epidemic killed approximately 20 to 40 million people over the world. In 2009, an outbreak of a new strain of H1N1 influenza infected more than one million people in Mexico, the deaths of more than ten thousand people were estimated, and the H1N1 influenza virus continuously spreads (Neumann, G.; Noda, T.; Kawaoka, Y. Emergence and Pandemic Potential of Swine-Origin H1N1 Influenza Virus. Nature. 459: 931-939, 2009). In addition, a special attention should be given to the invasion of seasonal influenza A virus subtype H3N2, which was marked in the Annual Meeting on National Influenza Prevention and Control, China in 2010 as the viral strain resulting in a number of deaths in the past.
Influenza virus is a negative-sense single stranded RNA virus that causes influenza in human and animals, which belongs to the Orthomyxoviridae family and can be classified into three serotypes, A, B and C according to their difference in viral nucleoproteins, hereditary materials and matrix protein antigenic properties, wherein influenza A virus causes influenza between different hosts due to polymorphism of both hemagglutinin (HA) and neuraminidase (NA) on its viral surface. It is currently found that hereditary antigenic variation may occur in 16 types of HA (H1˜16) and 9 NA (N1˜N9); influenza B virus antigenic variation is less frequent and only causes regional infection; the main host of influenza C is swine, where the infection of influenza C in human is rare; thus, the above-mentioned worldwide scale influenza is an epidemic caused by influenza A virus.
Structure of influenza A virus from the outside to the inside can be divided into three parts, being the envelope, matrix proteins and core. There are around 500 spikes radially arranged towards the outside on the envelope, which are the two types of the above-mentioned antigen: rod-like spikes (HA) and mushroom-like spikes (NA). HA can adhere to the surfaces of animal red blood cells to bind to various the receptors thereon and induce agglutination. HA can divide into heavy chain and light chain after cleavage, which makes the virus fuse with its host cells. NA has mainly a sialic acid hydrolysis activity, which removes the last connection between the virus and the host cells, causing the virus to shed from the red blood cells it is adhered to, preventing aggregation of the virus, promoting its movement in the mucus. Matrix proteins are composed of M1 and M2, having an effect of protection to the core and maintenance of the viral structure. Additionally, the core is composed of 8 negative-sense single stranded RNA, wherein it entwines and combines with nucleoproteins and RNA polymerase (PB1, PB2 and PA) to form ribosomes. The reason influenza virus causes people's panic is mainly because its ways of variation results in new subtypes and catches us by surprise, wherein there are two ways of variation, one being antigenic shift, which is a small variation caused by point mutation of the antigen (NA) amino acid sequence of the influenza virus subtype; another being antigenic shift, which is the most common type of influenza virus variation, where large scale antigenic variation happens every ten years, caused by the host infected with two different virus strains at the same time and recombination of viral RNA forms new virus strains, resulting in a large impact (Hong-Shan Chen, Xing-Quan Zhang, Antivirus Drug: Methods and Applications, Chemical Industry Press, 328-311, 2006).
Influenza usually occurs in autumn, winter and early spring, wherein its attacking target is respiratory tract mucous epithelial cells, and it will reproduce in host cells, which leads to pathological changes such as mucous hyperemia, edema, cell degeneration and detachment. There are usually 1 to 3 days in the latent period, some symptoms such as fever, shivering, headache, nasal obstruction, body ache, will appear. When the virus spreads to the lower respiratory tract, it may lead to bronchitis and interstitial pneumonia. As influenza virus will reduce the ability of respiratory tract mucous epithelial cells to remove and adhere foreign bodies, it often causes secondary pneumonia, which is one of the main reasons of death by influenza (Morens, D. M.; Taubenberger, J. K.; Fauci, A. S. Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness. J. Infect. Dis. 198: 962-970, 2008).
Currently, the most adopted preventions and treatments of influenza are community isolation and supportive drug therapy, and therapeutic prevention can be further characterized to vaccines and antiviral agents. However, for viruses which continue to vary, protection by vaccines still has its risks; there are mainly three types of antiviral agents, the first type being M2 protein inhibitors, which act on viral transmembrane M2 ion channel, blocking H+ from entering the virus, making the viral envelope unable to fuse with the endosome, thus the virus is incapable to release its RNA, where the type of drugs are adamantan derivatives, such as amantadine and rimantadine; the second type being neuraminidase (NA) inhibitors, which act on neuraminidase, making the virus unable to hydrolyse sialic acid, thus unable to leave its host cell, blocking spreading of the virus, where the type of drugs includes oseltamivir (Tamiflu), zanamivir (Relenza), peramivir and cyclopentane or pyrrolidine derivatives; the third type being RNA polymerase inhibitors, which mainly inhibit the pathway of RNA polymerase for synthesizing viral proteins, where the drugs include 2′-detoxy-2′-fluoroguanosine (FdG) and T-705; alternatively, there are also treatments to prevent viral infection by utilizing interferons and siRNA (small interfering RNAs) (Clereq, E. D. Antiviral Agents Active against Influenza A Viruses. Not. Rev. Drug. Discov. 5: 1015-1025, 2006).
However, all the above-mentioned drugs are unable to achieve comprehensive inhibition against all types of influenza viruses, and have deficiencies, such as drug resistance and side effects Influenza A having highly varied antigens, is highly infectious, where around 500 million people get infected every year, often causing a high death rate, resulting in a heavy burden and economic loss to the society, thus active development of new antiviral agents is indeed an important task.